Despite the development of several targeted agents, patients with advanced cancer that fail conventional therapies have an extremely poor prognosis. Identification of the mechanisms that contribute to therapeutic resistance is essential to improve clinical outcomes. Autophagy is a cell survival pathway that enables cells to recoup ATP and other forms of metabolic fuel by degrading damaged proteins and organelles. Autophagy may play a significant role in drug resistance by providing alternative energy sources to promote survival in the face of therapeutic stress. We recently established that the antimalarial drugs chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) inhibit autophagy and significantly increase the efficacy of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA). The TP53 tumor suppressor gene is frequently mutated/deleted in human tumors and its loss of function is associated with drug resistance and a poor clinical prognosis. Notably, the combination of HCQ and SAHA was equipotent in the presence and absence of functional TP53 in preclinical studies. In order to translate these findings into clinical benefit, we will conduct a Phase I, clinical pharmacokinetic (PK) and pharmacodynamic (PD) study of the combination of HCQ and SAHA in patients with advanced solid tumors. We hypothesize that the addition of HCQ will enhance the antitumor activity of SAHA without adding major toxicity. We propose 3 Specific Aims to test our hypothesis. In Specific Aim 1, we will investigate the safety, tolerability, and activity of HCQ in combination with SAHA in patients with advanced solid tumors. In Specific Aim 2, we will evaluate the PD of HCQ administrated in combination with SAHA with a series of correlative studies in peripheral blood mononuclear cells and tumor tissue from patients. We will quantify autophagy inhibition and the effects of treatment on key biomarkers associated with SAHA activity. The mutation status and copy number of TP53 will be determined to investigate a potential correlation between TP53 status and response rate. In Specific Aim 3, we will investigate the potential impact of HCQ on the PK of SAHA. The knowledge gained from these studies will provide a platform for future investigations with HCQ and other novel autophagy inhibitors. Inhibition of autophagy is an innovative anticancer strategy that targets an intrinsic vulnerability in cancer cells and has the potential to significantly impact the care of patients with advanced solid tumors and other treatment-refractory malignancies. Our study will immediately contribute to the NCI's mission to translate the findings of novel preclinical investigations into clinical benefit for cancer patients. PUBLIC HEALTH RELEVANCE: The inhibition of autophagy with hydroxychloroquine (HCQ) significantly enhances the anticancer activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in preclinical models. The proposed Phase I clinical trial will investigate the safety, tolerability, and activity of this novel therapeutic strategy in patients with advanced solid tumors. The proposed correlative studies will enable us to better understand the role of autophagy inhibition as an anticancer strategy. The knowledge gained from this investigation has the potential to significantly impact the care of patients with advanced solid tumors and other treatment- refractory malignancies and will provide a platform for future studies with HCQ and other novel autophagy inhibitors. )